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Down syndrome

Introduction to Down syndrome

The Chromosomal Basis of Down syndrome
Signs and Symptoms of Down Syndrome
The Occurrence of Down syndrome
Prenatal Screening and Diagnostic Testing
A Diagnosis of Down Syndrome
Down Syndrome and Associated Medical Disorders
Newborns
Infants and Preschool Children
Early Intervention and Education
Adolescence and Down syndrome
Adults with Down syndrome
Down Syndrome in the Workplace
Future Research in Down Syndrome
Questions and Answers About Down Syndrome
Additional Resources for Information on Down Syndrome

Down Syndrome
Named after John Langdon Down, the first physician to identify the syndrome, Down
syndrome is the most frequent genetic cause of mild to moderate mental retardation
and associated medical problems and occurs in one out of 800 live births, in all races
and economic groups. Down syndrome is a chromosomal disorder caused by an error
in cell division that results in the presence of an additional third chromosome 21 or
"trisomy 21."
The Chromosomal Basis of Down Syndrome
To understand why Down syndrome occurs, the structure and function of the human
chromosome must be understood. The human body is made of cells; all cells contain
chromosomes, structures that transmit genetic information. Most cells of the human
body contain 23 pairs of chromosomes, half of which are inherited from each parent.
Only the human reproductive cells, the sperm cells in males and the ovum in females,
have 23 individual chromosomes, not pairs. Scientists identify these chromosome
pairs as the XX pair, present in females, and the XY pair, present in males, and
number them 1 through 22.
When the reproductive cells, the sperm and ovum, combine at fertilization, the
fertilized egg that results contains 23 chromosome pairs. A fertilized egg that will
develop into a female contains chromosome pairs 1 through 22, and the XX pair. A
fertilized egg that will develop into a male contains chromosome pairs 1 through 22,
and the XY pair. When the fertilized egg contains extra material from chromosome
number 21, this results in Down syndrome.
The genetic variations that can cause Down syndrome
Three genetic variations can cause Down syndrome. In most cases, approximately
92% of the time, Down syndrome is caused by the presence of an extra chromosome
21 in all cells of the individual. In such cases, the extra chromosome originates in the
development of either the egg or the sperm. Consequently, when the egg and sperm
unite to form the fertilized egg, three--rather than two--chromosomes 21 are present.
As the embryo develops, the extra chromosome is repeated in every cell. This
condition, in which three copies of chromosome 21 are present in all cells of the
individual, is called trisomy 21.
In approximately 2%-4% of cases, Down syndrome is due to mosaic trisomy 21. This
situation is similar to simple trisomy 21, but, in this instance, the extra chromosome
21 is present in some, but not all, cells of the individual. For example, the fertilized
egg may have the right number of chromosomes, but, due to an error in chromosome
division early in embryonic development, some cells acquire an extra chromosome
21. Thus, an individual with Down syndrome due to mosaic trisomy 21 will typically
have 46 chromosomes in some cells, but will have 47 chromosomes (including an
extra chromosome 21) in others. In this situation, the range of the physical problems
may vary, depending on the proportion of cells that carry the additional chromosome
21.

Chromosome 21
In trisomy 21 and mosaic trisomy 21, Down syndrome occurs because some or all of
the cells have 47 chromosomes, including three chromosomes 21. However,
approximately 3%-4% of individuals with Down syndrome have cells containing 46
chromosomes, but still have the features associated with Down syndrome. How can
this be? In such cases, material from one chromosome 21 gets stuck or translocated
onto another chromosome, either prior to or at conception. In such situations, cells
from individuals with Down syndrome have two normal chromosomes 21, but also
have additional chromosome 21 material on the translocated chromosome. Thus,
there is still too much material from chromosome 21, resulting in the features
associated with Down syndrome. In such situations, the individual with Down
syndrome is said to have translocation trisomy 21.
Signs and Symptoms of Down Syndrome
Even though people with Down syndrome may have some physical and mental
features in common, symptoms of Down syndrome can range from mild to severe.
Usually, mental development and physical development are slower in people with
Down syndrome than in those without the condition.
Mental retardation is a disability that causes limits on intellectual abilities and
adaptive behaviors (conceptual, social, and practical skills people use to function in
everyday lives). Most people with Down syndrome have IQs that fall in the mild to
moderate range of mental retardation. They may have delayed language
development and slow motor development.
Some common physical signs of Down syndrome include:

Flat face with an upward slant to the eye, short neck, and abnormally shaped
ears

Deep crease in the palm of the hand

White spots on the iris of the eye
Poor muscle tone, loose ligaments
Small hands and feet

There are a variety of other health conditions that are often seen in people who have
Down syndrome, including:

Congenital heart disease

Hearing problems
Intestinal problems, such as blocked small bowel or esophagus
Celiac disease
Eye problems, such as cataracts
Thyroid dysfunctions
Skeletal problems
Dementia - similar to Alzheimer's

The Occurrence of Down Syndrome

Most of the time, the occurrence of Down syndrome is due to a random event that
occurred during formation of the reproductive cells, the ovum or sperm. As far as we
know, Down syndrome is not attributable to any behavioral activity of the parents or
environmental factors. The probability that another child with Down syndrome will be
born in a subsequent pregnancy is about 1 percent, regardless of maternal age.
The incidence of Down syndrome rises with increasing maternal age.
For parents of a child with Down syndrome due to translocation trisomy 21, there
may be an increased likelihood of Down syndrome in future pregnancies. This is
because one of the two parents may be a balanced carrier of the translocation. The
translocation occurs when a piece of chromosome 21 becomes attached to another
chromosome, often number 14, during cell division. If the resulting sperm or ovum
receives a chromosome 14 (or another chromosome), with a piece of chromosome 21
attached and retains the chromosome 21 that lost a section due to translocation,
then the reproductive cells contain the normal or balanced amount of chromosome

21. While there will be no Down syndrome associated characteristics exhibited, the
individual who develops from this fertilized egg will be a carrier of Down syndrome.
Genetic counseling can be sought to find the origin of the translocation.
However, it is important to realize that not all parents of individuals with translocation
trisomy 21 are themselves balanced carriers. In such situations, there is no increased
risk for Down syndrome in future pregnancies.
Researchers have extensively studied the defects in chromosome 21 that cause
Down syndrome. In 88% of cases, the extra copy of chromosome 21 is derived from
the mother. In 8% of the cases, the father provided the extra copy of chromosome
21. In the remaining 2% of the cases, Down syndrome is due to mitotic errors, an
error in cell division which occurs after fertilization when the sperm and ovum are
joined.
Down syndrome and maternal age
Researchers have established that the likelihood that a reproductive cell will contain
an extra copy of chromosome 21 increases dramatically as a woman ages. Therefore,
an older mother is more likely than a younger mother to have a baby with Down
syndrome. However, of the total population, older mothers have fewer babies; about
75% of babies with Down syndrome are born to younger women because more
younger women than older women have babies. Only about nine percent of total
pregnancies occur in women 35 years or older each year, but about 25% of babies
with Down syndrome are born to women in this age group.
The incidence of Down syndrome rises with increasing maternal age. Many specialists
recommend that women who become pregnant at age 35 or older undergo prenatal
testing for Down syndrome. The likelihood that a woman under 30 who becomes
pregnant will have a baby with Down syndrome is less than 1 in 1,000, but the
chance of having a baby with Down syndrome increases to 1 in 400 for women who
become pregnant at age 35. The likelihood of Down syndrome continues to increase
as a woman ages, so that by age 42, the chance is 1 in 60 that a pregnant woman
will have a baby with Down syndrome, and by age 49, the chance is 1 in 12. But
using maternal age alone will not detect over 75% of pregnancies that will result in
Down syndrome.
Relationship of Down Syndrome Incidence to Mother's Age
Mother's Age
Incidence of Down Syndrome
Under 30
less than 1 in 1,000
30
1 in 900
35
1 in 400
36
1 in 300
37
1 in 230
38
1 in 180
39
1 in 135
40
1 in 105
42
1 in 60
44
1 in 35
46
1 in 20
48
1 in 16
49
1 in 12
Source: Hook, E.G. Lindsjo, A. Down Syndrome in Live Births by Single Year Maternal
Age

Prenatal Screening for Down Syndrome

Prenatal screening for Down syndrome is available. There is a relatively simple,
noninvasive screening test that examines a drop of the mother's blood to determine
if there is an increased likelihood for Down syndrome. This blood test measures the
levels of three markers for Down syndrome: serum alpha feto-protein (MSAFP),
chorionic gonadotropin (hCG), and unconjugated estriol (uE3). While these
measurements are not a definitive test for Down syndrome, a lower MSAFP value, a
lower uE3 level, and an elevated hCG level, on average, suggests an increased
likelihood of a Down syndrome fetus, and additional diagnostic testing may be
desired.
Diagnostic testing for Down syndrome
There are several prenatal diagnostic tests that can be performed to determine the
occurrence of Down syndrome. These tests include amniocentesis, chorionic villus

sampling (CVS), and percutaneous umbilical blood sampling (PUBS). However, before
undergoing any of these diagnostic tests, patients and their families should seek
detailed genetic counseling to discuss their family history in relationship to the risks
and benefits of performing these diagnostic procedures.
Amniocentesis, the removal and analysis of a small sample of fetal cells from the
amniotic fluid, is widely available and involves a lower risk of miscarriage than
chorionic villus sampling. However, amniocentesis cannot be done until the 14th to
18th week of pregnancy, and it usually takes additional time to determine whether
the cells contain extra material from chromosome 21.
Chorionic villus sampling, conducted at 9 to 11 weeks of pregnancy, involves
extracting a tiny amount of chorionic villi, tissue extensions that will eventually
develop into a placenta. The tissue can be tested for the presence of extra material
from chromosome 21. The villi can be obtained through the pregnant woman's
abdomen or cervix. This type of sampling carries a 1-2% risk of miscarriage.
The third diagnostic method, percutaneous umbilical blood sampling or PUBS, is the
most accurate method and can be used to confirm the results of CVS or
amniocentesis. However, PUBS cannot be performed until later in the pregnancy,
during the 18th to 22nd weeks, and carries the greatest risk of miscarriage.
New prenatal diagnostic techniques are currently being developed. The NICHD has
supported the development of a new, noninvasive test performed during the first
trimester of pregnancy, that samples and separates fetal cells from the mother's
blood. The goal is to compare the accuracy of this type of cellular level analysis with
results obtained by amniocentesis or CVS.
Diagnostic tests for Down Syndrome
Amniocentesis

The removal and analysis of a small sample of fetal cells from the amniotic
fluid.

Cannot be done until the 14-18th week of pregnancy

Lower risk of miscarriage than chorionic villus sampling

Chorionic villus sampling (CVS)

Extraction of a tiny amount of fetal tissue at 9 to 11 weeks of pregnancy

The tissue is tested for the presence of extra material from chromosome 21
Carries a 1-2% risk of miscarriage

Percutaneous umbilical blood sampling (PUBS)

Most accurate method used to confirm the results of CVS or amniocentesis.

The tissue is tested for the presence of extra material from chromosome 21
PUBS cannot be done until the 18-22nd week
Carries the greatest risk of miscarriage

Researchers outside the NICHD are also developing a new method of diagnosis, called
preimplantation diagnosis or blastomere analysis before implantation (BABI), which
allows clinicians to detect chromosome imbalances before an embryo is implanted
during in vitro fertilization. This technique would primarily be used in couples who are
at risk of passing on X-linked disorders, couples who have suffered repeated
terminations of pregnancy, subfertile couples, or those at risk for single gene
disorders. This technique, which allows the clinician to provide a genetic diagnosis
prior to implantation, has been successful so far for cystic fibrosis, Tay Sachs disease,
and Lesch-Nyhan syndrome. BABI allows a couple to begin their pregnancy knowing
that the fetus is unaffected with the genetic disease of concern. For couples at high
risk, this procedure provides an alternative to prenatal testing in the first or second
trimester.
A Diagnosis of Down Syndrome
A newborn baby with Down syndrome often has physical features the attending
physician will most likely recognize in the delivery room. These may include a flat

facial profile, an upward slant to the eye, a short neck, abnormally shaped ears, white
spots on the iris of the eye (called Brushfield spots), and a single, deep transverse
crease on the palm of the hand. However, a child with Down syndrome may not
possess all of these features; some of these features can even be found in the
general population.
To confirm the diagnosis, the doctor will request a blood test called a chromosomal
karyotype. This involves "growing" the cells from the baby's blood for about two
weeks, followed by a microscopic visualization of the chromosomes to determine if
extra material from chromosome 21 is present.
Medical care for infants with Down syndrome should include the same well-baby care
that other children receive.
When parents are told that their newborn baby has Down syndrome, it is not unusual
for them to have feelings of sadness and disappointment. Many parents report that at
the time their child is first diagnosed with Down syndrome and during the weeks that
follow, they feel overwhelmed by feelings of loss and anxiety. While caring for a child
with Down syndrome frequently requires more time and energy, parents of newborn
children with Down syndrome should seek the advice of a knowledgeable pediatrician
and/or the many Down syndrome support groups and organizations available (see
Additional Resources for a listing).
The doctor making the initial diagnosis of Down syndrome has no way of knowing the
intellectual or physical capabilities this child, or any other child, may have. Children
and adults with Down syndrome have a wide range of abilities. A person with Down
syndrome may be very healthy or they may present unusual and demanding medical
and social problems at virtually every stage of life. However, every person with Down
syndrome is a unique individual, and not all people with Down syndrome will develop
all the medical disorders discussed below.
Down Syndrome and Associated Medical Disorders
During the first days and months of life, some disorders may be immediately
diagnosed. Congenital hypothyroidism, characterized by a reduced basal metabolism,
an enlargement of the thyroid gland, and disturbances in the autonomic nervous
system, occurs slightly more frequently in babies with Down syndrome. A routine
blood test for hypothyroidism that is performed on newborns will detect this condition
if present.
Several other well-known medical conditions, including hearing loss, congenital heart
disease, and vision disorders, are more prevalent among those with Down syndrome.
Recent studies indicate that 66 to 89% of children with Down syndrome have a
hearing loss of greater than 15 to 20 decibels in at least one ear, due to the fact that
the external ear and the bones of the middle and inner ear may develop differently in
children with Down syndrome. Many hearing problems can be corrected. But,
because of the high prevalence of hearing loss in children with Down syndrome, an
objective measure of hearing should be taken to establish hearing status. In addition
to hearing disorders, visual problems also may be present early in life. Cataracts
occur in approximately 3% of children with Down syndrome, but can be surgically
removed.
Approximately half of the children with Down syndrome have congenital heart
disease and associated early onset of pulmonary hypertension, or high blood
pressure in the lungs. Echocardiography may be indicated to identify any congenital
heart disease. If the defects have been identified before the onset of pulmonary
hypertension, surgery has provided favorable results.
Seizure disorders, though less prevalent than some of the other associated medical
conditions, still affect between 5 and 13% of individuals with Down syndrome, a 10fold greater incidence than in the general population. There is an unusually high
incidence of infantile spasms or seizures in children less than one year of age, some
of which are precipitated by neonatal complications and infections and cardiovascular
disease. However, these seizures can be treated with anti-epileptic drugs.
The incidence and severity of these associated medical ailments will vary in babies
with Down syndrome and some may require surgery.
Newborns

Babies with Down syndrome often have hypotonia, or poor muscle tone. Because
they have a reduced muscle tone and a protruding tongue, feeding babies with Down
syndrome usually takes longer. Mothers breast-feeding infants with Down syndrome
should seek advice from an expert on breast feeding to make sure the baby is getting
sufficient nutrition.
Hypotonia may affect the muscles of the digestive system, in which case constipation
may be a problem. Atlantoaxial instability, a malformation of the upper part of the
spine located under the base of the skull, is present in some individuals with Down
syndrome. This condition can cause spinal cord compression if it is not treated
properly.
Infants and Preschool Children
Medical care for infants with Down syndrome should include the same well-baby care
that other children receive during the first years of life, as well as attention to some
problems that are more common in children with Down syndrome. If heart, digestive,
orthopedic or other medical conditions were identified during the neonatal period,
these problems should continue to be monitored.
During the early years of life, children with Down syndrome are 10-15 times more
likely than other children to develop leukemia, a potentially fatal disease. These
children should receive an appropriate cancer therapy, such as chemotherapy.
Infants with Down syndrome are also more susceptible to transient myelodysplasia,
or the defective development of the spinal cord.
Compared to the general population, individuals with Down syndrome have a 12-fold
higher mortality rate from infectious diseases, if these infections are left untreated
and unmonitored. These infections are due to abnormalities in their immune systems,
usually the t-cell and antibody-mediated immunity functions that fight off infections.
Children with Down syndrome are also more likely to develop chronic respiratory
infections, middle ear infections, and recurrent tonsillitis. In addition, there is a 62fold higher incidence of pneumonia in children with Down syndrome than in the
general population.
Children with Down syndrome may be developmentally delayed. A child with Down
syndrome is often slow to turn over, sit, stand, and respond. This may be related to
the child's poor muscle tone. Development of speech and language abilities may take
longer than expected and may not occur as fully as parents would like. However,
children with Down syndrome do develop the communication skills they need.
Parents of other children with Down syndrome are often valuable sources of
information and support. Parents should keep in mind that children with Down
syndrome have a wide range of abilities and talents, and each child develops at his or
her own particular pace. It may take children with Down syndrome longer than other
children to reach develop mental milestones, but many of these milestones will
eventually be met. Parents should make a concerted effort not to compare the
developmental progress of a child with Down syndrome to the progress of other
siblings or even to other children with Down syndrome.
Early Intervention and Education
The term "early intervention" refers to an array of specialized programs and related
resources that are made available by health care professionals to the child with Down
syndrome. These health care professionals may include special educators, speech
therapists, occupational therapists, and social workers. It is recommended that
stimulation and encouragement be provided to children with Down syndrome.
The evaluation of early intervention programs for children with Down syndrome is
difficult, due to the wide variety of experimental designs used in interventions, the
limited existing measures available that chart the progress of disabled infants, and
the tremendous variability in the developmental progress among children with Down
syndrome, a consequence in part of the many complicating medical factors. While
many studies have been conducted to assess the effects of early intervention, the
information is limited and contradictory regarding the long-term success of early
intervention for children with Down syndrome.
However, federal laws (Public Law 94-142) are in place to ensure each state has as a
goal that "all handicapped children have available to them a free public education
and related services designed to meet their unique needs." The decision of what type
of school a child with Down syndrome should attend is an important one, made by

the parents in consultation with health and education professionals. A parent must
decide between enrolling the child in a school where most of the children do not have
disabilities (inclusion) or sending the child to a school for children with special needs.
Inclusion has become more common over the past decade.
Adolescence with Down Syndrome
Like all teenagers, individuals with Down syndrome undergo hormonal changes
during adolescence. Therefore, teenagers with Down syndrome should be educated
about their sexual drives. Scientists have medical evidence that males with Down
syndrome generally have a reduced sperm count and rarely father children. Females
with Down syndrome have regular menstrual periods and are capable of becoming
pregnant and carrying a baby to term.
Adults with Down Syndrome
The life expectancy for people with Down syndrome has increased substantially. In
1929, the average life span of a person with Down syndrome was nine years. Today,
it is common for a person with Down syndrome to live to age fifty and beyond. In
addition to living longer, people with Down syndrome are now living fuller, richer lives
than ever before as family members and contributors to their community. Many
people with Down syndrome form meaningful relationships and eventually marry.
Now that people with Down syndrome are living longer, the needs of adults with
Down syndrome are receiving greater attention. With assistance from family and
caretakers, many adults with Down syndrome have developed the skills required to
hold jobs and to live semi-independently.
Premature aging is a characteristic of adults with Down syndrome. In addition,
dementia, or memory loss and impaired judgment similar to that occurring in
Alzheimer disease patients, may appear in adults with Down syndrome. This
condition often occurs when the person is younger than forty years old. Family
members and caretakers of an adult with Down syndrome must be prepared to
intervene if the individual begins to lose the skills required for independent living.
Down Syndrome in the Workplace
The Americans with Disabilities Act (ADA) makes it illegal for an employer of more
than 15 individuals to discriminate against qualified individuals in application
procedures, hiring, advancement, discharge, compensation, job training, and other
terms of employment. The ADA requires that an employer provide reasonable
accommodation for individuals who are qualified for a position. More information
about the ADA can be obtained from the Office of Civil Rights of the U.S. Department
of Health and Human Services, Washington, DC, 20201.
Future Directions in Down Syndrome Research
Recently, it has been suggested that children with Down syndrome might benefit
from medical intervention that includes amino acid supplements and a drug known as
Piracetam. Piracetam is a psychoactive drug that some believe may improve
cognitive function. However, there have been no controlled clinical studies conducted
to date using Piracetam to treat Down syndrome in the U.S. or elsewhere that show
its safety and efficacy.
Down syndrome researchers have developed a mouse model to analyze the
developmental consequences of Down syndrome. Mice are used because a large
stretch of mouse chromosome 16 has many genes in common with those on human
chromosome 21. Studying these models at varying stages of development will
enhance our basic understanding of Down syndrome and facilitate the development
of effective interventions and treatment strategies.
Questions and Answers about Down Syndrome
1. Is Down syndrome a rare genetic disorder?
Down syndrome occurs in 1 in 800 births.
2. Do only older women give birth to babies with Down syndrome?
Researchers have established that the likelihood that a reproductive cell will contain
an extra copy of chromosome 21 increases dramatically as a woman ages. Therefore,
an older mother is more likely than a younger mother to have a baby with Down

syndrome, but older mothers account for only about 9% of all live births each year
and 25% of Down syndrome births.
3. Are all people with Down syndrome severely retarded?
Most people with Down syndrome have IQ's that fall in the mild to moderate range of
retardation. Some are so mildly affected that they live independently and are
gainfully employed.
4. Can people with Down syndrome receive proper care at home?
Home-based care and community living give them the opportunity to socialize and
benefit from such interactions.
5. Should all children with Down syndrome be placed in special education
classrooms?
While federal laws have been established to insure that all handicapped children
have access to public education, children with Down syndrome can and have been
included into a regular classroom.
6. Is there a cure for Down syndrome?
Researchers have identified the genes that cause the characteristics of Down
syndrome and are working to further develop mouse models, at varying stages of
development, in order to enhance their basic understanding of Down syndrome and
facilitate the development of effective interventions and treatment strategies.
Additional Resources for Down Syndrome
Information and Assistance
Administration on Developmental Disabilities
Administration for Children and Families
U.S. Department of Health and Human Services
Mail Stop: HHH 300F
370 L'Enfant Promenade S.W.
Washington, DC 20447
(202) 690-6590
http://www.acf.dhhs.gov/programs/add/
American Speech, Language and Hearing Association
10801 Rockville Pike
Rockville, MD 20852
1-800-638-8255 or 1-888-321-ASHA
http://www.asha.org/
Learning Disabilities Association of America
4156 Library Road
Pittsburgh, PA 15234-1349
(412) 341-1515 or 1-888-300-6710
http://www.ldanatl.org/
March of Dimes
1275 Mamaroneck Avenue
White Plains, NY 10605
(914) 428-7100
1-888-MODIMES (1-888-663-4637)
http://www.modimes.org/
National Down Syndrome Congress
1370 Center Drive, Suite 102
Atlanta, GA 30338
1-800-232-6372
(770) 604-9500
http://www.ndsccenter.org/
National Down Syndrome Society
666 Broadway
New York, NY 10012

1-800-221-4602
(212) 460-9330
http://www.ndss.org/
National Information Center for Children and Youth with Disabilities
P.O. Box 1492
Washington, DC 20013-1492
1-800-695-0285
(202) 884-8200
http://www.nichcy.org/
Mid-Atlantic Regional Human Genetics Network (MARHGN)
(genetic counseling)
Curtis Coughlin II, MS, MARHGN Coordinator
MARGHN c/o Christiana Health Care Services
Genetics Room 1988
4755 Ogletown-Stanton Road
P.O. Box 6001
Newark, DE 19718
(302) 733-6732
http://www.pitt.edu/~marhgn/
National Society of Genetic Counselors
233 Canterbury Drive
Wallingford, PA 19086-6617
(610) 872-7608
http://www.nsgc.org/
The Arc of the United States
1010 Wayne Avenue, Suite 650
Silver Spring, MD 20910
(301) 565-3842
(301) 565-3843 - Fax
http://www.thearc.org
SOURCE: national Institutes of Health, national Institute of Child Health and Human
Development

http://www.emedicine.com/ped/TOPIC615.HTM
Harold Chen, MD, MS, FAAP, FACMG, Professor, Department of Pediatrics, Chief,
Genetic Laboratory Services, Louisiana State University Medical
Center
Mortality/Morbidity

Approximately 75% of concepti with trisomy 21 die in embryonic or fetal life.

Approximately 85% of infants survive to age 1 year, and 50% can be expected
to live longer than age 50 years. Congenital heart disease is the most
important factor that determines survival. In addition, esophageal atresia with
or without transesophageal (TE) fistula, Hirschsprung disease, duodenal
atresia, and leukemia contribute to mortality. The high mortality rate later in
life may be the result of premature aging.
Individuals with Down syndrome have a greatly increased morbidity rate,
primarily because of infections involving impaired immune response. Large
tonsils and adenoids, lingual tonsils, choanal stenosis, or glossoptosis can
obstruct the upper airway. Airway obstruction can cause serous otitis media,
alveolar hypoventilation, arterial hypoxemia, cerebral hypoxia, and pulmonary
arterial hypertension with resulting cor pulmonale and heart failure.
A delay in recognizing atlantoaxial and atlanto-occipital instability may result
in irreversible spinal-cord damage. Visual and hearing impairments in addition
to mental retardation may further limit the child's overall function and may
prevent him or her from participating in important learning processes and
developing appropriate language and interpersonal skills. Unrecognized
thyroid dysfunction may further compromise CNS function.

Race
No racial predilection is known.
Sex

The male-to-female ratio is increased (approximately 1.15:1) in newborns with Down

syndrome. This effect is restricted to free trisomy 21.
Age

Down syndrome can be diagnosed prenatally with amniocentesis,

percutaneous umbilical blood sampling (PUBS), chorionic villus sampling
(CVS), and extraction of fetal cells from the maternal circulation.
Shortly after birth, Down syndrome is diagnosed by recognizing dysmorphic
features and the distinctive phenotype.

History
When recording the history from the parents of a child with Down syndrome, the
clinician should include the following: 3

Parental concern about hearing, vision, developmental delay, respiratory

infections, and other problems
Feeding history to ensure adequate caloric intake
Prenatal diagnosis of Down syndrome
Vomiting secondary to GI tract blockage by duodenal web or atresia
Absence of stools secondary to Hirschsprung disease
Delay in cognitive abilities, motor development, language development
(specifically expressive skills), and social competence
Arrhythmia, fainting episodes, palpitations, or chest pain secondary to heart
lesion
Symptoms of sleep apnea, including snoring, restlessness during sleep,
difficulty awaking, daytime somnolence, behavioral changes, and school
problems
Symptoms of atlantoaxial instability

o About 13-14% of patients have radiographic evidence of atlantoaxial

instability but no symptoms.
o Only 1-2% of patients have symptoms that require treatment.
o Symptoms include easy fatigability, neck pain, limited neck mobility or
head tilt, torticollis, difficulty walking, change in gait pattern, loss of
motor skills, incoordination, clumsiness, sensory deficits, spasticity,
hyperreflexia, clonus, extensor-plantar reflex, loss of upper-body
strength, abnormal neurologic reflexes, change in bowel and bladder
function, increased muscle tone in the legs, and changes in sensation
in the hands and feet.
o These symptoms often remain relatively stable for months or years.
o In rare cases, the symptoms progress to paraplegia, hemiplegia,
quadriplegia, or death.

Physical

Growth: Short stature and obesity occurs during adolescence.

CNS: Moderate-to-severe mental retardation occurs, with an intelligence
quotient (IQ) of 20-85 (mean, approximately 50). Hypotonia improves with
age. Articulatory problems are present. Sleep apnea occurs when inspiratory
airflow from the upper airway to the lungs is impeded for 10 seconds or
longer; it often results in hypoxemia or hypercarbia.
Behavior: Natural spontaneity, genuine warmth, cheerful, gentleness,
patience, and tolerance are characteristics. A few patients exhibit anxiety and
stubbornness.
Seizure disorder (5-10%): Infantile spasms are the most common seizures
observed in infancy, whereas tonic-clonic seizures are most common in older
patients.
Premature aging: Decreased skin tone, early graying or loss of hair,
hypogonadism, cataracts, hearing loss, age-related increase in
hypothyroidism, seizures, neoplasms, degenerative vascular disease, loss of
adaptive abilities, and increased risk of senile dementia of Alzheimer type are
observed.
Skull: Brachycephaly, microcephaly, a sloping forehead, a flat occiput, large
fontanels with late closure, a patent metopic suture, absent frontal and
sphenoid sinuses, and hypoplasia of the maxillary sinuses occur.
Eyes: Up-slanting palpebral fissures, bilateral epicanthal folds, Brushfield spots
(speckled iris), refractive errors (50%), strabismus (44%), nystagmus (20%),

blepharitis (33%), conjunctivitis, tearing from stenotic nasolacrimal ducts,

congenital cataracts (3%), pseudopapilledema, spasm nutans, acquired lens
opacity (30-60%), and keratoconus in adults are observed.
Nose: Hypoplastic nasal bone and flat nasal bridge are typical characteristics.
Mouth and teeth: An open mouth with a tendency of tongue protrusion, a
fissured and furrowed tongue, mouth breathing with drooling, a chapped lower
lip, angular cheilitis, partial anodontia (50%), tooth agenesis, malformed
teeth, delayed tooth eruption, microdontia (35-50%) in both the primary and
secondary dentition, hypoplastic and hypocalcified teeth, malocclusion,
taurodontism (0.54-5.6%), and increased periodontal destruction are noted.
Ears: The ears are small with an overfolded helix. Chronic otitis media and
hearing loss are common. About 66-89% of children have a hearing loss of
greater than 15-20 dB in at least 1 ear, as assessed by means of the auditory
brainstem response (ABR).
Neck: Atlantoaxial instability (14%) can result from laxity of transverse
ligaments that ordinarily hold the odontoid process close to the anterior arch
of the atlas. Laxity can cause backward displacement of the odontoid process,
leading to spinal cord compression in about 2% of children with Down
syndrome.
Chest: The internipple distance is decreased.
Congenital heart defects: Congenital heart defects are common (40-50%);
they are frequently observed in patients with Down syndrome who are
hospitalized (62%), and they are a common cause of death in this aneuploidy
in the first 2 years of life. The most common congenital heart defects are
endocardial cushion defect (43%), ventricular septal defect (32%), secundum
atrial septal defect (10%), tetralogy of Fallot (6%), and isolated patent ductus
arteriosus (4%). About 30% of patients have several cardiac defects. The most
common lesions are patent ductus arteriosus (16%) and pulmonic stenosis
(9%). About 70% of all endocardial cushion defects are associated with Down
syndrome.
Abdomen: Diastasis recti and umbilical hernia occur.
GI system (12%): Duodenal atresia or stenosis, Hirschsprung disease (<1%),
TE fistula, Meckel diverticulum, imperforate anus, and omphalocele are
observed. The prevalence rate of celiac disease in individuals with Down
syndrome is reportedly 5-15% in different European and US studies. Celiac
disease occurs in genetically susceptible individuals, specifically those who
have the HLA heterodimers DQ2 (observed in 86-100% of individuals with
celiac disease) and DQ8. These are strong linkages with high sensitivity and
poor specificity.
Genitourinary tract: Renal malformations, hypospadias, micropenis, and
cryptorchidism occur.
Skeleton: Short and broad hands, clinodactyly of the fifth fingers with a single
flexion crease (20%), hyperextensible finger joints, increased space between
the great toe and the second toe, and acquired hip dislocation (6%) are typical
presentations.
Endocrine system: Hypothyroidism (16-20% of young patients), diabetes, and
decreased fertility occur. Thyroid disorders, such as congenital
hypothyroidism, primary hypothyroidism, autoimmune thyroiditis, and
compensated hypothyroidism or hyperthyrotropinemia, have been reported to
have a prevalence rate of 3-54% in individuals with Down syndrome
and increase in frequency with increasing age.
Hematologic system

o The relative risk of acute leukemia in the first 5 years of life is 56 times
that of individuals without Down syndrome. Approximately one in 150
patients develops leukemia. Neonatal leukemoid reactions (ie,
pseudoleukemia) are common, and distinguishing this from true
leukemia frequently poses a diagnostic challenge.
o Transient myeloproliferative disorder (TMD) associated with
pancytopenia, hepatosplenomegaly, and circulating immature WBCs, is
found almost exclusively in infants who have Down syndrome, with an
incidence rate of approximately 10%. TMD spontaneously regresses
within the first 3 months of life. However, in some children, it can be
life threatening. Despite the high rate of spontaneous regression, TMD
can be a preleukemic disorder in 20-30% of children with Down
syndrome.
o Acute myeloid leukemia (AML) is as common in these individuals as
acute lymphoid leukemia (ALL). Acute megakaryocytic leukemia
(AMKL) is the most common form of AML in affected children and is
uncommon in children who do not have Down syndrome.
o Although the risk for leukemia is higher in individuals with Down
syndrome, these patients have a lower risk of developing solid tumors,

with the exception of germ cell tumors and, perhaps, retinoblastomas

and lymphomas.
o The patient's risk of carrying hepatitis B is increased if previously
institutionalized.
Immunodeficiency: Patients have about a 12-fold increased risk of infectious
diseases, especially pneumonia, because of impaired cellular immunity.
Skin: Xerosis, localized hyperkeratotic lesions, elastosis serpiginosa, alopecia
areata (<10%), vitiligo, folliculitis, abscess formation, and recurrent skin
infections are observed.
Dermatoglyphics: Distal axial triradius in the palms, transverse palmar
creases, a single flexion crease in the fifth finger, ulnar loops (often 10), a
pattern in hypothenar, and interdigital III regions are observed.
Neurobehavioral disorders: Most children with Down syndrome do not have a
coexisting psychiatric or behavioral disorder. The available estimates of
psychiatric comorbidity range from 18-38%. The disorders include attention
deficit hyperactivity disorder, oppositional defiant disorder, nonspecific
disruptive disorder, autism spectrum disorders, and stereotypical movement
disorder in prepubertal children with Down syndrome and depressive illness,
obsessive-compulsive disorder, and psychoticlike disorder in adolescents and
adults with Down syndrome
Genetic counseling
o
o
o

Trisomy 21: If the couple has a child with trisomy 21, the risk of
recurrence is about 1%. The risk does not appear to be increased in
siblings of affected individuals.
Translocation Down syndrome: If the child has a translocation, a
balanced translocation must be excluded in the parents.
Robertsonian translocation: In cases of de novo Robertsonian
translocation, the risk of Down syndrome in a subsequent pregnancy is
an estimated 2-3%. If either parent has a translocation, start additional
family studies and counseling. A parent with a balanced Robertsonian
translocation is phenotypically normal but has an increased risk of
having a chromosomally unbalanced offspring. The theoretic
recurrence risk for a Robertsonian carrier parent to have a liveborn
offspring with Down syndrome is 1 in 3. However, only 10-15% of the
progeny of carrier mothers and only 2-3% of the progeny of carrier
fathers have Down syndrome. The reason for this difference is not
clear. In a carrier parent with a 21q21q translocation or
isochromosome, the recurrence risk is 100%.
Mosaic Down syndrome: Most patients with mosaic Down syndrome
were once trisomy 21 zygotes. The phenotype varies and possibly
reflects the variable proportion of trisomy 21 cells in the embryo during
early development. In rare instances, low-level mosaicism in germinal
tissue of a parent is postulated to be the cause of more than 1 trisomic
child in the family.
Reproduction: Affected individuals rarely reproduce. About 15-30% of
females with trisomy 21 are fertile, and they have a 50% risk of having
an affected child. The literature contains reports of 4 pregnancies
fathered by 3 male patients with Down syndrome. Infertility in males
has been attributed to defective spermatogenesis, but ignorance of the
sexual act may be one of the contributing factors.